Abstract The objective of this proposal is to validate a new regenerative tissue matrix which studies to date indicate may be possible of redefining the limits of autologous fat grafting. This objective is motivated by the currently limited surgical options available to the 6 million patients undergoing reconstructive plastic surgery each year to treat body disfigurement and dysfunction. A core component of many reconstructive procedures is filling a void with tissue, and the use of autologous fat grafts, with their innate biocompatibility and low procedural risk, has gained popularity. Despite their increase in favorable outcomes, obtaining consistent results has proved a significant challenge. For example, patients undergoing post-mastectomy breast reconstruction require an average of greater than 2 surgeries for procedural completion because of insufficient available volume of soft tissue or resorption due to insufficient vascularization. While attempts have been made to improve initial graft success rates by combining autologous tissue with synthetic polymers or patient-derived decellularized tissue, these attempts have met with minimal success due to lack of intrinsic bioactivity, high cost, or long processing times. Recombinant protein polymers are an unexplored but promising alternative, whereby mimics of naturally occurring extracellular matrix proteins can be recombinantly synthesized at high yield with molecular level control of their properties?a precision far superior to synthetic polymers. Motivated by this clear clinical need, this proposal seeks to optimize and test a recently developed innovative biomatrix ?Fractomer? composed of an artificial recombinant protein designed to mimic native elastin. The Fractomer biomatrix is thermally responsive, allowing it to be injected as a liquid, but to rapidly phase transition in vivo to form a porous, fractal network at body temperature. Preliminary studies have shown that this matrix is biocompatible, with minimal inflammation, no fibrous capsule formation, excellent tissue integration, and the rapid formation of the branching neovascular networks essential for tissue graft success. Our central hypothesis is that the Fractomer matrix can stability integrate with and increase the effective volume of adipose tissue, maximizing graft success while reducing the required amount of autologous tissue. The following research strategy will be pursued in clinically relevant small animal models as a precursor to clinical implementation: purified fat prepared from human lipoaspirate at Duke University Hospital will be mixed with a Fractomer solution at different ratios in athymic mice, and monitored for up to 6 months. The cellular composition and long term stability of the Fractomer matrix will be directly compared with both fat grafting and commercial hyaluronan gels with the goal of demonstrating permanent retention of higher graft volumes. Graft weight, volume, and cellular composition?as determined by a combination of computed tomography and histology?will be used to evaluate graft success. The technology proposed here offers a basis for solving the fundamental issues associate with fat graft reliability, and, if successful, would significantly reduce the necessity of secondary surgical procedures.